Journal
FASEB JOURNAL
Volume 35, Issue 4, Pages -Publisher
WILEY
DOI: 10.1096/fj.202002594R
Keywords
apoptosis; cell cycle; microtubule-targeting agents; oral squamous cell carcinoma; Wnt/beta-catenin signaling
Categories
Funding
- JC Bose National Fellowship [JCB/2019/000016]
- Department of Science and Technology, Government of India
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The study demonstrates that microtubule-targeting agents inhibit the signaling of beta-catenin in oral squamous cell carcinoma, leading to a decrease in cancer malignancy. Additionally, the combined use of these agents with Wnt/beta-catenin signaling antagonists shows promise as a strategy for cancer chemotherapy.
An aberrant accumulation of nuclear beta-catenin is closely associated with the augmentation of cancer malignancy. In this work, we report that several microtubule-targeting agents (MTAs) such as vinblastine, taxol, and C12 (combretastatin-2-aminoimidazole analog) inhibit VvUt/beta-catenin sienaline in oral squamous cell carcinoma (OSCC). We showed that the inhibition of microtuhule dynamics by MTAs decreased the level of beta-catenin by increasing Axin and adenomatous polyposis coli levels and reducing the level of dishevelled. Furthermore, MTAs strongly reduced the localization of beta-catenin in the nucleus. The reduction in the level of nuclear beta-catenin was neither due to the degradation of beta-catenin in the nucleus nor due to an increase in the export of nuclear beta-catenin from the nucleus. A motor protein kinesin-2 was found to assist the nuclear transportation of beta-catenin. Interestingly, Wnt/beta-catenin signaling antagonist treatment synergized with MTAs and the activators of Wnt/beta-catenin signaling antagonized with the MTAs. C12 potently suppressed the growth of 4-Nitroquinoline 1-oxide-induced OSCC in the tongue of C57 black 6 mice and also abrogated Wnt/beta-catenin signaling pathway in the tumor. Our results provide evidence that the decrease in Wnt/beta-catenin signaling is an important antitumor effect of MTAs and the combined use of MTAs with Wnt/beta-catenin signaling antagonists could be a promising strategy for cancer chemotherapy.
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